A main objective of this project is to explore the biochemical pathophysiology of depressive disorders through studies of catecholamine output and metabolism. An empirically derived discriminant function equation (D-type equation) based on urinary catecholamines and metabolites, has been shown to discriminate bipolar manic-depressive depressions from other subtypes, and recent findings suggest that this equation may have even broader clinical applicability (e.g., as a predictor of differential antidepressant responses to treatment with imipramine or alprazolam). In another phase of this research, it was found that depressed patients with high catecholamine output showed heterologous (agonist nonspecific) desensitization of the adenylate cyclase (AC) enzyme complex in platelets, that was corrected during successful treatment with alprazolam. Continuing these lines of investigation, the goals of the proposed research are: 1) To test the hypothesis that the D-type equation or other equations generated by discriminant function techniques based on urinary catecholamines and metabolites can predict response to the "noradrenergic" antidepressant DMI, and to explore whether an equation can be found to predict response to the "serotonergic" antidepressant fluoxetine; 2) To confirm that catecholamine levels are inversely correlated with measures of platelet AC activity and to explore whether catecholamine-induced heterologous desensitization of AC activity is mediated by prostaglandins (PG); 3) To test the hypothesis that depressed patients with high catecholamine output who respond to DMI by 6 weeks will show decreased urinary norepinephrine levels, decreased PG levels and increased platelet AC activity after only one week of DMI; 4) To explore the pattern of longitudinal changes in urinary catecholamines and metabolites, PG levels and platelet AC activity in relationship to response to DMI; 5) To examine the influence of platelet MAO activity an the hypothalamic pituitary adrenocortical (HPA) axis on the relationship between catecholamines and platelet AC activity; 6) To explore the effects of fluoxetine on longitudinal changes in urinary catecholamines and metabolites, PG levels, measures of platelet AC activity, platelet MAO activity, the HPA axis and clinical response in depressed patients; 7) To perform studies parallel to aims 2, 3, 4, 5 and 6 above, using peripheral blood mononuclear cells. It is expected that these studies will further the development of a biochemical classification of depressive disorders that provides a more rational basis for selecting effective antidepressant treatment.